In the past year, we have investigated the use of physiological and mechanical promoters to enhance the delivery of a radioimmunotherapeutic agent, Y-90 labeled B3 monoclonal antibody directed against Lewis Y antigen, to an antigen-positive solid tumor, thereby improving the therapeutic efficacy. As physiological promoters, we used Taxol, a plant alkaloid which promotes the stabilization (polymerization) of microtubules leading to mitotic arrest at a radiosensitive G2/M phase that disrupts cell division process and causes cell death, and Bevacizumab (Avastin), an anti-angiogenic monoclonal antibody directed against vascular endothelial growth factor (VEGF). As a mechanical promoter, we used pulsed high intensity focused ultrasound (p-HIFU) exposure. In our initial studies, we previously found that a combination therapy of Y-90-B3 with Taxol produced a synergistic effect in the shrinkage of tumor size whereas the p-HIFU exposure on tumors provided an additive effect to the Y-90-B3 treatment. We extended these studies to 120 days and also investigated if an addition of the anti-angiogenic agent Avastin to a combined therapy of Y-90-B3 with Taxol would be beneficial in prolongation of a median survival time. Methods: Groups of nude mice (n = 5-9 mice/group) were inoculated s.c. with A431 tumor cells expressing the LewisY antigen on the right hind flank. When the tumor size was 200 cubic mm, the mice received i.v. Y-90-labeled B3 alone (60 micro-Ci/150 micro-g B3 or 100 micro-Ci/150 micro-g B3), i.p. Taxol alone (40 micro-g/kg), i.v. Avastin alone (5 mg/kg), two agents together (Y-90-labeled B3 and after 24 hr, Taxol or Avastin and after 24 hr, Y-90-labeled B3), and three agents together (Avastin, Y-90-labeled B3 and Taxol at 1 day intervals), or no treatment. To investigate the effect of p-HIFU, the tumor was treated first with pulsed-HIFU, and within 10 min after p-HIFU, the mice received i.v. Y-90-labeled B3 with or without Taxol. The tumor volume and the body weight were measured daily for the first 7 days and thereafter, two or three times a week. Mice were euthanized when the tumor size was 2 cm in diameter. Results: The control mice had a median survival time of 5 days. The Taxol and Avastin treatment delayed tumor growth with a median survival time of 17 days and 11 days, respectively. The Y-90B3 treatment showed a dose-dependent response with a median survival time of 18 days for the 60 Ci B3 group and 29 days for the 100 Ci B3 group. The combined therapy involving 60 Ci B3 and 100 Ci B3 with Taxol showed a striking synergistic effect in shrinking tumor and prolonging the survival time. The p-HIFU combined with 60 Ci B3 treatment prolonged a median survival time to 26 days, comparable to that of animals treated with 100 Ci B3 alone. The addition of Avastin before 60 Ci B3 treatment produced a median survival time of 20 days. On day 120, 3 of 9 mice (33%) treated with a combined therapy involving 60 Ci B3 and Taxol, and 6 of 6 mice treated with a combined therapy of 100 Ci B3 with Taxol were alive with no tumor. The addition of Avastin treatment or p-HIFU exposure to the combined therapy of 60 Ci B3 and Taxol provided some additive effect in survival; 3 of 6 (50%) treated with Avastin and 4 of 7 (57%) treated with p-HIFU were alive with no tumor. Conclusion: The combined therapy involving Y-90 B3 and Taxol produced a striking synergistic effect whereas the addition of p-HIFU or Avastin treatment to Y-90 B3 treatment produced an additive effect. This synergistic effect of Taxol and the additive effect of p-HIFU or Avastin to the radioimmunotherapy warrant further studies in other tumor models.